The vertebrate synapse is a specialized form of cell-cell contact critical in nervous system function. The plasma membrane and underlying associated cytoplasmic proteins of both the pre- and postsynaptic sides of the synapse form highly specialized, ultrastructurally unique complexes that are the intracellular locations of many of the biochemically and physiologically regulated synaptic events. The proposed study is designed to examine the molecular organization of the cortical cytoplasm and associated synaptic plasma membrane within central nervous system presynaptic terminals. This will be accomplished by the powerful combination of three, well-documented technologies: a) labelling of presynaptic, subcellular compartments within the terminal by axonal transport, b) the enrichment of radiolabeled presynaptic terminals by careful and rigorous preparation of synaptosomes and c) the subjection of these radiolabled synatosomes to a battery of experiments, similar to those previously used to elucidate the structural organization of the spectrin-enriched cytoskeleton and the associated plasma membrane of the red blood cell. Information we may thus obtain through basic research on normal biochemistry, molecular organization, and functioning of the synapse will aid A) in understanding the way the presynaptic terminal performs its important biological tasks under the stress of disease states, and B) in discerning the origins and source of malfunctions that affect the synapse directly.